An antibody-drug conjugate (ADC) is an antibody drug in which an antibody is bound to a drug and which aims to efficiently deliver the drug to a disease site by utilizing the antigen specificity of the antibody, and in recent years, it is one of the most rapidly growing techniques in the field of cancer treatment. The ADC is composed of each part of an antibody, a drug and a linker for binding between the antibody and the drug.
The linker plays a role to stably bind the antibody and the drug until the ADC reaches the target site, and on the other hand, the linker is required to have a function in many cases that it is selectively cleaved at the target site to detach the drug from the antibody. As such cleavable linkers, an acid hydrolyzable linker which is cleaved in a low pH environment in the cell, a disulfide linker which is cleaved in a reductive environment in the cell, a dipeptide linker which is cleaved by increased expression of enzymes in the cancer cell and the like have been developed.
Hitherto, as the acid hydrolyzable linker in the field of ADC, a hydrazone linker is mainly used. Including Mylotarg (registered trademark) which has received at first the FDA approval as the ADC, the hydrazone linkers are introduced into ADCs currently in clinical trial stage.
However, it is reported that the hydrazone linker is hydrolyzed during blood circulation and the drug is released in sites other than the target site, and as a result, there is a possibility of causing side effects, for example, systemic toxicity or organ specific toxicity. It is believed that this is caused by instability of the hydrazone in pH of the blood (Non-Patent Document 1).
In Patent Document 1, it is described that the hydrolysis rate of hydrazone can be regulated by changing substituents on the benzene ring in the vicinity of the hydrazone, and antibody-drug conjugates having several kinds of hydrazone linkers having different substituents on the benzene ring are disclosed. However, evaluation data of the hydrolysis rate are not shown.
Moreover, in Non-Patent Document 2, kinetics study of the hydrolysis of hydrazone is described and it is shown that in the hydrolysis of hydrazone, the influence of differences in the substituents present on the neighboring benzene ring on the hydrolysis rate is small. Therefore, there is a possibility that the hydrazone is not the best choice for the purpose of regulating the hydrolysis rate.
As other acid hydrolyzable linkers used for ADC, an ester linker (Non-Patent Document 3) and a silyl ether linker (Non-Patent Document 4) are reported, but these are not linkers which are able to regulate the hydrolysis rate to match a variety of pH values.
As described above, there has been no example relating to an acid hydrolyzable linker in which the hydrolysis rate is able to be accurately controlled in accordance with the pH of the target site in the living body.